The long-term goal ofthe research program. Genetic Models for Precision Cancer Medicine (Drs. Bult, Dai, and McKeon co-Leaders), is to develop novel therapeutic and diagnostic concepts for cancer by modeling and interrogating the complex genomics of human cancers. Research is organized around three inter-related themes, all of which involve the systems genomics ofthe cancer cell and its host environment. The first theme. Cancer Cell Robustness, aims to define the dynamic genome alterations at a systems level that generate primary drug resistance in a cancer and its subclones. The second theme. Genetic and Genomic Complexity, aims to measure and quantify genomic instability in primary cancers;to describe the associated genomic configurations;and to use defective maintenance systems for genome integrity for therapeutic advantage. The third theme. Progenitor Cell Biology, aims to define the genomic parameters of certain cancer progenitors;to reconstruct cancer states in primary cells using systems approaches;and to use this knowledge to provide effective combinatorial therapeutics. All program goals rely on interactions with program members who are developing advanced cross cutting technological approaches. The first approach, precision model development, includes efficient methods for humanizing cancer-relevant genomic regions in the mouse;tool strains for directing and visualizing temporal and tissue-specific gene expression;optimized immunodeficient mice for sustained engraftment of primary human cancers;and populations of mice that model human genomic heterogeneity. The second approach, genomic technologies, develops new high throughput DNA interrogation methodologies for detailed assessment of structural and sequence mutations and their transcriptional consequences. The third key technology is computational, including algorithms for modeling gene networks;ontology development that supports data integration and enables in silico modeling of gene functional associations;and informatics and database systems are essential for integrative studies and comparative genomic analyses. The 47 program members include 35 at Bar Harbor, 8 at Farmington, and 1 at Sacramento, together with 3 adjunct members from UC Davis Comprehensive Cancer Center, Eastern Maine Healthcare Systems, and Trinity University (TX). Through its emphasis on basic research and unique technology development, the program leverages funding from multiple NIH ICs in support of cancer focused research. In total the program is supported by $40,150,131 total costs in NCI and other peer reviewed cancer-related support in the last budget year. Over the past grant cycle, program members produced 1022 publications, including 10% intra-programmatic collaborations and 62% with collaborators external to JAX

Public Health Relevance

The JAXCC member retreat serves as the forum for planning that brings together all Cancer Center members from all campuses. Topics include collaborative projects;new resource and model development;technological and methodological innovations and their application to cancer research;and research areas for faculty recruiting, among others. Partial CCSG funding for the JAXCC member retreat is requested.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Center Core Grants (P30)
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Subcommittee G - Education (NCI)
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Jackson Laboratory
Bar Harbor
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Rutherford, Sarah C; Fachel, Angela A; Li, Sheng et al. (2018) Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations. Blood 132:e13-e23
Barthel, Floris P; Wesseling, Pieter; Verhaak, Roel G W (2018) Reconstructing the molecular life history of gliomas. Acta Neuropathol 135:649-670
Winer, Benjamin Y; Shirvani-Dastgerdi, Elham; Bram, Yaron et al. (2018) Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection. Sci Transl Med 10:
Kim, Hyunsoo; Kumar, Pooja; Menghi, Francesca et al. (2018) High-resolution deconstruction of evolution induced by chemotherapy treatments in breast cancer xenografts. Sci Rep 8:17937
Schechter, Lisa M; Creely, David P; Garner, Cherilyn D et al. (2018) Extensive Gene Amplification as a Mechanism for Piperacillin-Tazobactam Resistance in Escherichia coli. MBio 9:
Barthel, Floris P; Johnson, Kevin C; Wesseling, Pieter et al. (2018) Evolving Insights into the Molecular Neuropathology of Diffuse Gliomas in Adults. Neurol Clin 36:421-437
Vian, Laura; P?kowska, Aleksandra; Rao, Suhas S P et al. (2018) The Energetics and Physiological Impact of Cohesin Extrusion. Cell 173:1165-1178.e20
Tarchini, Basile; Longo-Guess, Chantal; Tian, Cong et al. (2018) A spontaneous mouse deletion in Mctp1 uncovers a long-range cis-regulatory region crucial for NR2F1 function during inner ear development. Dev Biol 443:153-164
Garrett, Andrew M; Khalil, Andre; Walton, David O et al. (2018) DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members. Proc Natl Acad Sci U S A 115:E10216-E10224
Huang, Bin; Jia, Dongya; Feng, Jingchen et al. (2018) RACIPE: a computational tool for modeling gene regulatory circuits using randomization. BMC Syst Biol 12:74

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